Antigenic and genetic characterization of the novel influenza A H1N1 virus indicated that the virus contained a unique combination of gene segments from North American and Eurasian lineages of swine influenza viruses. The viruses isolated from human cases of the 2009 pandemic H1N1 (pH1N1) virus infection were antigenically homogeneous and antigenically similar to North American swine H1N1 viruses, but distinct from seasonal human influenza A H1N1 viruses. The hypothesis of original antigenic sin (OAS) states that the imprint established by an individuals first influenza infection governs the antibody response thereafter. Subsequent influenza virus infections result in an antibody response against the original infecting virus, impairing the immune response against a newer influenza virus. A live attenuated influenza virus (LAIV) vaccine is licensed for healthy adults 2-49 years of age. This vaccine is administered by nasal spray. Neutralizing antibody in the serum has been found to be a correlate of protection for TIV, but the immune correlates of protection for LAIV are not known. Defining the origin and nature of transcriptional responses to LAIV in upper respiratory tract will be a highly informative first step in a systems approach toward understanding the molecular basis of viral replication restriction and the regulation of the local mucosal immune responses following LAIV administration. In FY13, in collaboration with colleagues at Stanford University, we undertook a natural history study using a systems biology approach to identify LAIV replication niches among a variety of URT cell types and characterize the host immune response to LAIV. Data analysis is in progress. Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine containing A/California/07/09 H1N1, A/Perth/16/09 H3N2, B/Brisbane/60/08. Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. In conclusion, LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis.